Streptococcus mutans is recognized as the principal etiological agent of dental caries, the most prevalent infectious disease of humans. The ability to metabolize carbohydrates and generate acids, to survive acidic pH and other adverse conditions, and to adhere to and form tenacious biofilms on the tooth surface are believed to be critically associated with the cariogenicity of this human pathogen. Known for its high degree of acid tolerance (aciduricity) and its high capacity to produce acid (acidogenicity), S. mutans lives primarily on the tooth surface at high cell-density in a high diversity ecosystem better known as dental plaque, the structure and composition of which is known to be largely influenced by such factors as the source and availability of nutrients, the pH in the oral cavity and by the ability of the biofilm organisms to adapt to the fluctuations in environmental conditions. Quorum sensing is a cell density--dependent regulatory mechanism that is known to be involved in regulation of a variety of physiologic processes and virulence in both Gram (+) and Gram (-) bacteria. We have recently generated evidence that the S. mutans possesses a gene encoding a functional homologue of the new family of autoinducer synthases (LuxS) that are responsible for production of autoinducers of the quorum sensing system 2, AI-2. This study is designed to yield novel information concerning LuxS-mediated quorum sensing and virulence regulation in S. mutans, which will contribute to our understanding of the pathogenesis of this microorganism and the ecology of the oral flora. The Specific Aims of this proposed study are: 1) to investigate the role of luxS in acid tolerance by S. mutans. By using functional assays, reporter gene fusions, Northern hybridization, and proteomics, we will investigate acid tolerance and its regulation by luxS, and identify novel factors (proteins) that are involved in luxS-regulated acid tolerance responses. 2). To use confocal laser scanning microscopy (CLSM) and mixed, known-species consortia to determine the impact of luxS of S. mutans on bacterial adherence by S. mutans and the inter- and intra-generic interactions between S. mutans and other oral bacteria in terms of biofilm initiation development and structure.